Millions of HIV-infected individuals in sub-Saharan Africa now receive life-saving antiretroviral therapy (ART), but mortality remains high. We have recently identified the indole 2,3-dioxygenase-1 (IDO) tryptophan catabolism pathway - which has recently been implicated as an important determinant of HIV pathogenesis - as a strong predictor of mortality in this setting. The goal of this proposal is to characterize the long-term impact of suppressive ART on this pathway, to characterize the immunologic mechanisms that mediate its association with morbidity and mortality, and to assess the contributions of prevalent co-infections to this pathway in vivo, to identify targets for novel interventions in this setting.We will address these issues in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort, a study of over 500 HIV-infected individuals initiating their first ART regimen in Mbarara, Uganda, which plans to enroll an additional 250 participants over the next 2 years. In preliminary data from this cohort, we have already observed a strong, independent relationship between the extent of indole 2,3-dioxygenase (IDO)-induced tryptophan catabolism inflammatory pathway (both pre-ART and during early viral suppression) and subsequent mortality. However, the degree to which IDO induction remains abnormal during long-term ART- mediated viral suppression, the specific immunologic mechanisms mediating the relationship between IDO- induced tryptophan catabolism and morbidity/mortality, and the degree to which prevalent co-infections including intestinal helminthes, malaria, and CMV contribute to this pathway in vivo remain unclear. To address these issues, we will assess the degree to which this pathway remains abnormal despite 5 years of suppressive antiretroviral therapy compared to a cohort of age-, gender-, and sub-county-matched cohort of 100 HIV-uninfected Ugandans (Aim 1), the immunologic mediators of the association between IDO-induced tryptophan catabolism and both mortality and incident TB (Aim 2), and the impact of chronic/recurrent asymptomatic co-infections including helminthes, malaria, and CMV on IDO-induced tryptophan catabolism (Aim 3). This study will be the first to fully characterize the contribution of the IDO pathway to morbidity and mortality in sub-Saharan Africans initiating ART and will identify specific targets for interventions to further decrease morbidity and mortality in this setting, where the majority o HIV-infected individuals live.